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Original Investigation
September 2018

Interactive Associations of Vascular Risk and β-Amyloid Burden With Cognitive Decline in Clinically Normal Elderly Individuals: Findings From the Harvard Aging Brain Study

Author Affiliations
  • 1Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston
  • 2Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston
  • 3Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston
  • 4J. Philip Kistler Stroke Research Center, Massachusetts General Hospital, Boston
  • 5Center for Alzheimer Research and Treatment, Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
  • 6Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia
  • 7Melbourne School of Psychological Sciences, University of Melbourne, Parkville, Victoria, Australia
  • 8Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston
JAMA Neurol. 2018;75(9):1124-1131. doi:10.1001/jamaneurol.2018.1123
Key Points

Question  Is vascular risk associated with prospective cognitive decline in a cohort of clinically normal older adults, additively or synergistically with β-amyloid?

Findings  In this study, Framingham and other vascular risk algorithms were associated with longitudinal cognitive decline, both alone and synergistically with β-amyloid burden. Vascular risk maintained a strong association with cognitive decline beyond that of commonly used imaging biomarkers, including β-amyloid, hippocampal volume, fludeoxyglucose F18–labeled positron emission tomography, and white matter hyperintensities.

Meaning  Vascular risk may complement other imaging biomarkers in assessing risk of cognitive decline in older adults with preclinical Alzheimer disease.

Abstract

Importance  Identifying asymptomatic individuals at high risk of impending cognitive decline because of Alzheimer disease is crucial for successful prevention of dementia. Vascular risk and β-amyloid (Aβ) pathology commonly co-occur in older adults and are significant causes of cognitive impairment.

Objective  To determine whether vascular risk and Aβ burden act additively or synergistically to promote cognitive decline in clinically normal older adults; and, secondarily, to evaluate the unique influence of vascular risk on prospective cognitive decline beyond that of commonly used imaging biomarkers, including Aβ burden, hippocampal volume, fludeoxyglucose F18–labeled (FDG) positron emission tomography (PET), and white matter hyperintensities, a marker of cerebrovascular disease.

Design, Setting, and Participants  In this longitudinal observational study, we examined clinically normal older adults from the Harvard Aging Brain Study. Participants were required to have baseline imaging data (FDG-PET, Aβ-PET, and magnetic resonance imaging), baseline medical data to quantify vascular risk, and at least 1 follow-up neuropsychological visit. Data collection began in 2010 and is ongoing. Data analysis was performed on data collected between 2010 and 2017.

Main Outcomes and Measures  Vascular risk was quantified using the Framingham Heart Study general cardiovascular disease (FHS-CVD) risk score. We measured Aβ burden with Pittsburgh Compound-B PET. Cognition was measured annually with the Preclinical Alzheimer Cognitive Composite. Models were corrected for baseline age, sex, years of education, and apolipoprotein E ε4 status.

Results  Of the 223 participants, 130 (58.3%) were women. The mean (SD) age was 73.7 (6.0) years, and the mean (SD) follow-up time was 3.7 (1.2) years. Faster cognitive decline was associated with both a higher FHS-CVD risk score (β = −0.064; 95% CI, −0.094 to −0.033; P < .001) and higher Aβ burden (β = −0.058; 95% CI, −0.079 to −0.037; P < .001). The interaction of the FHS-CVD risk score and Aβ burden with time was significant (β = −0.040, 95% CI, −0.062 to −0.018; P < .001), suggesting a synergistic effect. The FHS-CVD risk score remained robustly associated with prospective cognitive decline (β = −0.055; 95% CI, −0.086 to −0.024; P < .001), even after adjustment for Aβ burden, hippocampal volume, FDG-PET uptake, and white matter hyperintensities.

Conclusions and Relevance  In this study, vascular risk was associated with prospective cognitive decline in clinically normal older adults, both alone and synergistically with Aβ burden. Vascular risk may complement imaging biomarkers in assessing risk of prospective cognitive decline in preclinical Alzheimer disease.

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